Trichloro pregnadienes and esters thereof



United States Patent 3,415,855 TRICHLORO PREGNADIENES AND ESTERS THEREOFElliot L. Shapiro, Cedar Grove, and Emanuel B.

Hershberg, West Orange, N.J., assignors to Schering Corporation,Bloomfield, N.J., a corporation of New Jersey No Drawing. Filed May 27,1966, Ser. No. 566,699 9 Claims. (Cl. 260--397.45)

ABSTRACT OF THE DISCLOSURE This invention relates to9a,11B,l6a-trichloro-l,4-pregnadiene-17a,21-diol-3,20-dione, to Cl7and/or C-21 esters thereof and to methods for preparing the same; saidcompounds being useful as anti-inflammatory agents.

This invention relates to new compositions of matter classifiable in thefield of steroid chemistry as l6a-chloro- 9,1l-dihalo corticoids and theesters thereof, and to the use of these compositions in the applicationof antiinflammatory therapy.

In one of its composition aspects the instant invention may be describedas residing in the concept of a steroid compound having the molecularstructure of a 90:1,llfi,16a-trichloro-1,4-pregnadiene-l7ct,21-diol-3,20-dione and to the17-lower alkanoyl esters thereof and the 21-pharmaceutically acceptableesters thereof and the 1704,2l-diesters thereof.

In another of its composition aspects the instant invention may bedescribed as residing in the concept of a pharmaceutical formulationcontaining as an essential active ingredient a tangible embodiment asdescribed above.

The instant invention is based upon the discovery that the tangibleembodiments disclosed herein elicit a potent anti-inflammatory effect asdetermined by standard pharmacological evaluation. This effect isespecially pronounced when the tangible embodiments are administered viathe topical route.

The novel compounds of the instant invention in one sense may berepresented as a member of the group consisting of 1,4-pregnadieneshaving the following structural formula:

wherein R is hydrogen or lower alkanoyl and R is hydro gen, phosphono,sulfo, hydrocarbon carbonyl having up to 12 carbon atoms andcarboxysubstituted-hydrocarbon carbonyl having up to 12 carbon atoms.

As used herein the term lower alkanoyl denotes acyl groups of alkanoicacids having up to carbon atoms including straight and branched chainacids.

Similarly, the term hydrocarbon carbonyl denotes acyl groups ofhydrocarbon carboxylic acids and, as used herein, those groups derivedfrom such acids having up to 12 carbon atoms. Exemplary of the foregoingare such acids as acetic, propionic, pivalic, valeric,cyclopropylcarboxylic, adamantoic, benzoic, phenylacetic and the like.The term carboxysubstituted-hydrocarbon carbonyl denotes hemi-acylgroups derived from dibasic hydrocar- 3,415,855 Patented Dec. 10, 1968'bon carboxylic acids of up to 12 carbon atoms such as result from theesterification of a steroidal C-21 hydroxyl group with such acids assuccinic, malonic, maleic, malic, glutaric, adipic and the like; maleicand succinic being preferred.

As used herein the terms phosphono and sulfo denote the monovalent andthe monovalent -s oH groups respectively.

The tangible embodiments of this invention may be prepared from16ot-chloro-l,4-pregnadiene-11;8,l7ot,21- triol-3,20-dione 21-acetate,which upon dehydration via known methods is transformed into16ot-chloropregnatriene-17a,21-diol-3,20 dione ZI-acetate. Chlorinationof the 9,1l-double bond by known techniques yields a tangible embodimentof Formula I in the form of its 21-acetate. This compound may optionallybe hydrolyzed by treatment with aqueous acid in a Water miscible organicsolvent or saponified with aqueous alkali. Aqueous perchloric acid inmethanol is preferred to perform this transformation yielding the free21-hydroxy analog.

The l'iot,2l-di-ester embodiments of this invention wherein the estergroups are derived from the same acid function are readily obtained byknown esterification techniques from the corresponding 170t,21-dl01. Thel7a,2l-dipropionate of904,11B,16a-trichloro-1,-4-pregnadiene-17u,2l-diol-3,20-dione may beprepared, for example, by treating the diol with a mixture of trifluoroacetic anhydride and propionic acid at about C. for about 1 to about 2hours followed by precipitation to yield the l7ot,2l-dipropionate.

The di-esters of the instant invention wherein the ester groups at the17a and 21 positions are dissimilar, are also readily prepared byconventional esterification techniques. By starting with thetrichloro-l7a,2l-diol embodiment and esterifying at the 21 position witha lower alkanoyl chloride or anhydride in a tertiary amine, the 21-monoester is obtained. The ester function at position 17 may be formed byreacting the 21-mono-ester with either a lower alkanoic acid incombination with trifluoroacetic anhydride or with a mixture of a loweralkanoic acid and its anhydride in the presence of a strong acidcatalyst such as p-toluene sulfonic acid or mineral acid as representedby perchloric or sulfuric acid.

Alternatively, both 17-mon0esters and 17,21-diesters (having similar ordissimilar acyl moieties) may be prepared through a 17,21-orthoesterintermediate. In this method the 9a,11,8,l6a-trichloro-1,4-pregnadiene-17oz,21- diol-3,20-dione is treated with a lower alkyl ester of anorthocarboxylic acid, such as methyl orthobutyrate, in the presence of astrong acid catalyst to form the corresponding 17,21-orthoester whichupon mild acid hydrolysis is converted to the correspondingl7-tmonoester. Introduction of an ester function at C-2l, which mayeither be the same as or different from the ester function at C]7, isreadily accomplished by methods previously described.

It is to be understood that in the examples appearing hereinafter thatin these examples disclosing the preparation of ZI-hemisuccinateembodiments the products obtained are not washed free of acid, since theembodiment itself contains a free carboxylic acid group.

The best mode contemplated by applicant for carrying out this inventionis set forth in the following examples.

Example 1.-901,11B,1601-trichloro-1,4-pregnadiene 1701,21-diol-3,20-dione 21-acetate (A) Dissolve 711 mg. of1601-chloro-1,4-pregnadiene- 11fl,l701,21-triol 3,20 dione 21 acetate(1601 chloroprednisolone 21-acetate) and 338 mg. N-bromacetamide in 7.1ml. pyridine. Maintain this solution at room temperature for 10 minutes.Cool this solution to and bubble sulfur dioxide into it until thesolution becomes very dark. This usually takes approximately 5 minutes.Discontinue the sulfur dioxide addition and allow the reaction mixtureto stand at 5 for approximately minutes. Precipitate the crude productby adding water and extract the precipitate with methylene chloride.Wash the methylene chloride extract with dilute hydrochloric acid, thenwith water until the washes are neutral and dry the extract overanhydrous magnesium sulfate. Filter the sus' pension and evaporate thefiltrate to a residue. Triturate the residue with ether and collect theinsolubles. Crystallize the insolubles from ethyl acetate to obtain 564mg.

of 1601-chloro-1,4,9(11)-pregnatriene-1701,21-diol 3,20- dione2l-acetate. M.P. 225228 C., [01] +4 (1% in CHCl (B) Dissolve 430 mg. ofthe triene obtained above in ml. methylene chloride and 4.5 ml.pyridine. Cool the solution to with stirring. Add very rapidly 0. 86 ml.of a solution of chlorine in carbon tetrachloride, said solution havinga chlorine titer of mg. per milliliter of solution. Allow the reactionto proceed for 2 hours then raise the temperature of the reactionmixture up to 10 and allow the reaction to continue for an additional 3hours. Dilute the reaction mixture with methylene chloride to 150milliliter total volume. Wash the methylene chloride solution withdilute hydrochloric acid and with Water until the washes are neutral.Dry the organic solvent layer over anhydrous magnesium sulfate. Removethe inorganic salts by filtration and evaporate the filtrate to aresidue. Crystallize the residue from ethyl acetate to obtain 315 mg. ofthe compound of this example.

Example 2.901,11,8,1601-trichloro-1,4-pregnadiene 1701, 21diol-3,2Odione Dissolve mg. of the product of Example 1 in 7.0 ml.methyl alcohol and 0.18 ml. 70% perchloric acid. Allow the reactionmixture to remain at room temperature for 18 hours. Add salt water tothe solution and extract with methylene chloride. Wash the methylenechloride extract with a 5% solution of sodium carbonate solution andwith water. Evaporate the organic layer to a residue and crystallize theresidue from acetone-hexane to yield901,11B,1601-trichloro-1,4-pregnadiene-1701,21 diol 3,20- dione.

Example 3.901,l1p,l601-trichloro-1,4-pregnadiene 1701,21-diol-3,20-dione 17-propionate Treat 5 g. of 901,11,8,1601-trichloro-1,4-pregnadiene-1701, 21-di0l-3,20-dione in 500 ml. ofbenzene with 3.0 ml. of trimethylorthopropionate and mg. ofpara-toluenesulfonic acid monohydrate at reflux /2 hour. Cool thesolution to room temperature and add 5.0 g. of sodium bicarbonate and5.0 ml. of triethylamine. Stir the mixture for five minutes and filter.Concentrate the filtrate to a residue and dissolve the residue withexternal cooling in 50 ml. of 95% acetic acid 5% water mixture. Stir themixture at room temperature for 15-20 hours. Precipitate the product bydilution with 10 volumes of water. Collect the product by filtration andWater wash the precipitate free of acid. Purify the crude product bycrystallization from acetone obtaining the 17-propionate of thisexample.

In like manner, by employing other lower alkyl orthocarboxylic acidesters in the process of this example, additional l7-esters are preparedsuch as the acetate from methylorthoacetate; the butyrate from methyl orethyl orthobutyrate, and the valerate from a lower alkyl orthovalerate.

Example 4.901,11B,l601-trichloro-1,4-pregnadiene 1701, 2l-diol3,20-dione17-propionate 21-valerate Dissolve 1 g. of901,1lfi,1601trichloro-1,4-pregnadienel701,2l-diol-3,2O-dione1701-propionate in 5 ml. of dry pyridine and 1 ml. of valeric anhydride.Allow the reaction mixture to remain at room temperature for 18 hours.Precipitate the product by pouring the reaction mixture slowly into 50ml. of vigorously stirred ice water solution containing 6 m1. ofconcentrated hydrochloric acid. Collect the product by filtration andwash it free of excess acid. The mixed diester product of this exampleis purified by crystallization from acetone'hexane.

In like manner, by employing appropriate acid anhydrides or acidchlorides in the process of this example and using the 1701-esters asprepared in Example 3, 17-21- diesters of which the following areexemplary are prepared:

901,11,8,l601-trichloro-1,4-pregnadiene-1701,21-diol-3,20-

dione 17,2 l-diacetate901,11B,1601-trichloro-1,4-pregnadiene-1701,2l-diol-3,20-

dione l7-acetate 2 l -propionate901,l113,1601-trichloro-1,4-pregnadiene-l701,2l-di0l-3 ,20-

dione l7-acetate 2 l-butyrate 901, l 1,8,l601-trichloro-1,4-pregnadiene-1701,21-di0l-3 ,20-

dione l7-acetate 2 l -valerate901,11e,l601-trichloro-1,4-pregnadiene-l701,2l-diol-3 ,20-

dione 1701-acetate 21-enanthate 901,11B,1601-trichloro-1,4-pregnadiene-1701,2l-diol-3 ,20-

dione 17-acetate 21-hemisuccinate901,11,8,1601-trichloro-l,4-pregnadiene-1701,21-diol-3 ,20-

dione l7-acetate 2 l-cyclopropylcarboxylate 901,1 1e,l601-trichloro-1,4-pregnadiene-l701,21-diol-3,20-

dione 17-propionate 21-acetate 901,11/3,1601-trichloro-1,4-pregnadiene-1701,21-diol-3,20-

dione 17,21-dipropionate901,11B,1601-trichloro-1,4-pregnadiene-1701,2l-diol-3,2O-

dione 17-butyrate 21-propionate901,11,8,1601-trichloro-1,4-pregnadiene-l701,2l-dio1-3,20-

dione 17-propionate 21-butyrate 901,11B,1601-trichloro-1,4-pregnadiene-1701,21-diol-3,20-

dione 17-propionate 2 l -valerate901,1lB,l601-trichloro-1,4-pregnadiene-1701,2l-diol-3,2O-

dione l7-propionate 2 1 -enanthate901,11,8,1601-trichloho-l,4-pregnadiene-1701,21-diol-3,20-

dione 17-propionate 21-cyclopropylcarboxylate901,116,l601-trichloro-l,4-pregnadiene-l701,2l-diol-3,2O-

dione l7-propionate 2 l-hexanoate901,11,8,1601-trichloro-1,4-pregnadiene-1701,21-di0l-3 ,20-

dione 17-butyrate 21-acetate901,11B,1601-trichloro-1,4-pregnadiene-1701,21-di01-3 ,20-

dione 17,21-dibutyrate901,11B,1601-trichloro-1,4-pregnadiene-l701,21-diol-3,2O-

dione 17-butyrate 21-valerate 901,11&1601-trichloro-1,4-pregnadiene-1701,2l-di0l-3 ,20-

dione 17-valerate 21acetate901,11/3,1601-trichloro-1,4-pregnadiene-1701,21-diol-3,20-

dione 17-valerate 2 l-propionate901,11,8,l601-trichloro-1,4-pregnadiene-l701,21-diol-3,20-

dione 17,21-divalerate Example5.901,11,8,l601-trichloro-1,4-pregnadiene-1701, 21-dio1-3,20-dione17,21-dibutyrate Suspend 10 g. of 901,11p,1601-trichloro-1,4-pregnadiene1701,2l-diol-3,20-dione in ml. of butyric acid, add 50 ml. oftrifiuoroacetic anhydride, and warm the mixture on a steam bath to about80 C. and hold at temperature for 1 hour. Cautiously add 50 ml. of waterand allow 10 minutes for the decomposition of the excess anhydride andcool the reaction mixture to room temperature. Pour the acid solutionslowly into 2.0 l. of vigorously stirred ice water to precipitate theproduct. Collect this product on a filter, wash it until the washes areessentially neutral. The product obtained thereby comprises the titlecompound which may be crystallized from ethyl acetate.

In like manner, by employing the procedure and the starting material ofthis example and utilizing acetic, propionic, isobutyric or valericacids in combination with trifiuoroacetic anhydride, 17,2l-diesters areprepared such as the 17,21-diacetate, 17,21-dipropionate,17,2l-diisobutyrate, 17,21-divalerate, and the like.

Example 6.-9u,l 113,] 6vt-trichloro-1,4-pregnadiene-l7a,2l-diol-3,20-dione l7-valerate 2l-acetate Suspend 5 g. of9a,11B,16a-trichl0ro-1,4-pregnadienel70c,2l-dlOl-3,Z0-dl0ll6 21-acetatein 50 ml. of valeric acid. Add 25 ml. of trifiuoroacetic anhydride andwarm the mixture on a steam bath for 1 hour at 80 C. Cool the mixture toroom temperature and add 25 ml. of water. Allow 10 minutes for thedecomposition of the excess anhydride and pour the reaction mixtureslowly into 1.0 l. of ice water with vigorous agitations. Collect theproduct by filtration and wash it free of excess acid. The productobtained in this manner comprises the title compound and minor amountsof insoluble impurities which may be removed by crystallization fromaqueous methanol.

In like manner, by the appropriate selection of the ester function at 21of the starting material and the requisite carboxylic acid incombination with trifluoro acetic anhydride and by using the process ofthis example, cliesters may be prepared of which the following areexemplary:

911,1 15,16u-trichloro-1,4-pregnadiene-l7a,21-diol-3,20-

dione l7-butyrate 2 l-propionate 9a,l1p,l6a-trichloro-1,4-pregnadiene-17a,2l-dio1-3,20-

dione l7-butyrate 2l-valerate 911,11B,l6a-trichloro-l,4-pregnadiene-l7a,21-diol-3,20-

dione l7-valerate 21-propionate9a,11B,16a-trichloro-1,4-pregnadiene-17a,21-diol-3,20-

dione 17-acetate 21-valerate9ot,11B,16a-trichloro-l,4-pregnadiene-l7a,21-diol3,20-

dione 17-acetate 2l-butyrate90,11,8,16a-trichloro-1,4-pregnadiene-17ot,21-diol-3,20-

dione 17-propionate 2l-acetate9a,11B,16u-trichloro-1,4-pregnadiene-17a,2l-diol-3,20-

dione 17,21-dipropionate 90:,11,6,l6a-trichloro-l,4-pregnadiene-17a,21-diol-3,20-

dione l7-valerate 21-hemissucinate 911,1119,16a-trichloro-1,4-pregnadiene-17a,2l-diol-3,20-

dione 17-valerate 2 l-cyclopropylcarboxylate Example7.9mt,l16,16ot-trichloro-l,4-pregnadiene-17u, 2l-diol 3,20-dione21-adamantoate Dissolve 10 g. of adamantane carboxylic acid in 4 ml. oftrifiuoroacetic anhydride. Add to this solution 1 gm. of 9a,11 8,16atrichloro l,4-pregnadiene-17a,21-diol-3,20- dione prepared as in Example2. Stir the resulting solution at 25 C. for 1 hour and precipitate bypouring slowly into ml. of water. Collect the precipitate on a filterand water wash. Dry the product and slurry the dry solids in 100 ml. ofhexane for 1 hour. Filter the suspen sion, re-slurry the solids in ml.of fresh hexane for 1 hour and re-filter the suspension. Crystallize theremaining solids from acetone-hexane to obtain9a,1l/3,l6ot-U'lchloro-l,4-pregnadiene-17rx,2l-diol-3,20-dioneZI-adamantoate.

The tangible embodiments of this invention elicit a potentanti-inflammatory elfect in animals and humans as determined by standardpharmacological testing tech niques. They are of particular use whenapplied topically. The topical utility of a 17a,21-diol, such as amember of the tangible embodiments described herein is particularlysurprising, for such alcohols generally are relatively inactive via thisroute of application.

The tangible embodiments of this invention may be applied topically inthe form of ointments, lotions and creams and aerosol sprays. Theseformulations may also contain perfumes and be colored with appropriatetints to approximate skin color.

Desirably these formulations are compounded so as to contain from about.05 to about 1.0% by weight of steroid, 0.1% to 0.3% by weight beingespecially preferred.

The effective dosage of the tangible embodiments described hereindepends upon the severity, the stage and the individual characteristicsof each case and should be determined by a physician or a veterinarian.In general, however, the compounds of the instant invention may beapplied topically from 1 to about 4 times a day.

Where a systemic effect is to be elicited, the tangible embodiments mayalso be administered in the form of tablets, capsules, elixirs andinjectable suspensions or solutions. These dosage forms may,additionally, contain anti-anxiety medicaments to minimize the anxietiesoften coincident with an inflammatory condition.

The following formulations are for illustrative purposes only and arenot to be construed as in any way limiting this invention.

Aerosol formulation 50 gram container .3% steroid does:

911,115,160: trichloro-1,4-pregnadiene-1711,21-

diol-3,20-dione' ZI-ace'tate mg 6.0 Isopropyl myristate gms 1.994 Freon11 (35%) Freon 12 (65%) q.s. to .500 gms.

Add to the isopropyl myristate, in a suitable container, the previouslymicronized steroid and mix by gentle rotary agitation. Premix the freonpropellants in the indicated ratio and add to the product mix in thecontainer to a net weight of 50 g.

Vanishing cream Parts 9oz,1l,B,l6ot trichloro-1,4-pregnadiene1704,21-(1101-3,

20-dione ZI-adamantoate 2.5 Stearic acid 100 Span 60 50 Span 10 Tween 3030 Methyl paraben USP 1.0 Butyl paraben USP 4.0

Distilled water q.s. to 1000 parts.

Tablet-5 mg.

9a,11B,l6oc trichloro-1,4-pregnadiene l7w,2ldiol- 3,20-dione 17-valerateZI-acetate 5.0 Starch, food 5.0 Lactose (spray dried), USP 89.5Magnesium stearate 0.5

Mix the starch and the steroid, the latter having been previously milledin a suitable mixing vessel, and add an equal weight of lactose. Blenduntil uniform and then transfer to a larger mixing vessel containing theremainder of the lactose. Blend the mixture until homogeneous. Remove aportion (10-20 mg.) and blend with the magnesium stearate. Add themagnesium stearate mix to the balance of the steroid blend preparedabove and com press to desired specifications.

Lactose (spray dried), USP Magnesium stearate, USP 0.5

The steroid is milled to a uniform, fine particle size (150400 mesh) andmixed with approximately 1% of the lactose in a suitable mixingcontainer. This premix is added to the remainder of the lactose in alarger blending vessel, blended until uniform and used to fill hardshell slip capsules.

It is to be understood that the foregoing formulations have beenpresented for the purpose of illustration and that other tangibleembodiments of this invention would be utile in the formulationspresented. It should be further understood that in the variouspharmaceutical compositions presented herein the concentration of theactive ingredient will be such that an amount of composition which canbe conveniently administered during each treatment will contain asufficient quantity of such active ingredient which will elicit anappropriate and proper therapeutic response.

We claim:

1. A compound selected from the group consisting of 1,4-pregnadieneshaving the following structural formula:

wherein R is a member selected from the group consisting of hydrogen andlower alkanoyl, and R is a member selected from the group consisting ofhydrogen, phosphono, sulfo, hydrocarbon carbonyl, andcarboxysubstituted-hydrocarbon carbonyl, said hydrocarbon carbonylgroups having up to 12 carbon atoms.

2. A compound of claim 1 wherein R is lower alkanoyl and R is hydrogen.

3. A compound of claim 1 wherein R is hydrogen and R is adamantoyl, saidcompound being 90,1lfi,16a-tri chloro 1,4pregnadiene-l7a,21-diol-3,20-dione 2l-adamantoate.

4. A compound of claim 1 wherein R is propionyl and R is propionyl, saidcompound being 9a,11fi,16u-trichloro 1,4 pregnadiene17a,2l-diol-3,20-dione 17,21- dipropionate.

5. A compound of claim 1 wherein R is butyrate and R is butyrate, saidcompound being 9a,11;6,16a-trichloro-1,4-pregnadiene-17a,21-diol-3,20-dione 17,21-dibutyrate.

6. A compound of claim 1 wherein R is propinoyl and R is hydrogen, saidcompound being 9oz,l1/3,16ot-trichloro 1,4 pregnadiene 17a,21diol-3,20-dione 17 propionate.

7. A compound of claim 1 wherein R is butyryl and R is hydrogen, saidcompound being 9a,11/3,16u-trichlor0-1,4-pregnadiene-l7u,21-diol-3,20-dione l7-butyrate.

8. A compound of claim 1 wherein R is valeryl and R is hydrogen, saidcompound being 9a,11fi,16u-trichloro-1,4-pregnadiene-l7u,21-diol-3,20-dione 17-valerate.

9. A compound of claim 1 wherein R and R are hydrogen, said compoundbeing 911,11fi,16a-trichloro-1,4- pregnadiene-17a,2l-diol-3,20-dione.

No references cited.

ELBERT L. ROBERTS, Primary Examiner.

U.S. Cl. X.R.

